Correspondence between altered functional and structural connectivity in the contralesional sensorimotor cortex after unilateral stroke in rats: a combined resting-state functional MRI and manganese-enhanced MRI study

This study shows a significant correlation between functional connectivity, as measured with resting-state functional magnetic resonance imaging (MRI), and neuroanatomical connectivity, as measured with manganese-enhanced MRI, in rats at 10 weeks after unilateral stroke and in age-matched controls. Reduced interhemispheric functional connectivity between the contralesional primary motor cortex (M1) and ipsilesional sensorimotor cortical regions was accompanied by a decrease in transcallosal manganese transfer from contralesional M1 to the ipsilesional sensorimotor cortex after a large unilateral stroke. Increased intrahemispheric functional connectivity in the contralesional sensorimotor cortex was associated with locally enhanced neuroanatomical tracer uptake, which underlines the strong link between functional and structural reorganization of neuronal networks after stroke

White matter fractional anisotropy values from seed-based analysis of fractional anisotropy maps.

<p>DTI fractional anisotropy was measured in four different white matter seed regions. Boxplots display for 5-HTT^-/- and 5-HTT^+/+ animals the average value in each of the regions. Fractional anisotropy was significantly lower in the genu of the corpus callosum of 5-HTT^-/- animals (two-sample <i>t</i>-test, <i>t</i>  =  -3.33, false discovery rate (FDR)-adjusted <i>p</i> < 0.05).</p

Stress-induced alterations in large-scale functional networks of the rodent brain

Stress-related psychopathology is associated with altered functioning of large-scale brain networks. Animal research into chronic stress, one of the most prominent environmental risk factors for development of psychopathology, has revealed molecular and cellular mechanisms potentially contributing to human mental disease. However, so far, these studies have not addressed the system-level changes in extended brain networks, thought to critically contribute to mental disorders. We here tested the effects of chronic stress exposure (10. days immobilization) on the structural integrity and functional connectivity patterns in the brain, using high-resolution structural MRI, diffusion kurtosis imaging, and resting-state functional MRI, while confirming the expected changes in neuronal dendritic morphology using Golgi-staining. Stress effectiveness was confirmed by a significantly lower body weight and increased adrenal weight. In line with previous research, stressed animals displayed neuronal dendritic hypertrophy in the amygdala and hypotrophy in the hippocampal and medial prefrontal cortex. Using independent component analysis of resting-state fMRI data, we identified ten functional connectivity networks in the rodent brain. Chronic stress appeared to increase connectivity within the somatosensory, visual, and default mode networks. Moreover, chronic stress exposure was associated with an increased volume and diffusivity of the lateral ventricles, whereas no other volumetric changes were observed. This study shows that chronic stress exposure in rodents induces alterations in functional network connectivity strength which partly resemble those observed in stress-related psychopathology. Moreover, these functional consequences of stress seem to be more prominent than the effects on gross volumetric change, indicating their significance for future research

Cocaine-induced activation pattern from voxel-based analysis of pharmacological MRI.

<p>BOLD-based pharmacological MRI was performed for 50 minutes, with 1 mg/kg cocaine injected intravenously after 10 minutes. The maps display the group-level results from a voxel-based analysis of cocaine-induced brain activation, obtained from second-level analysis of subject-level generalized least squares fits of the pharmacological MRI signals in (A) 5-HTT^+/+, and (B) 5-HTT^-/- animals. The maps display <i>Z</i>-values of significantly activated voxels (<i>p</i> < 0.01, cluster-corrected). Positive responses are color-coded between <i>Z</i>  =  [2.3, 6.3], and overlaid on a multi-slice anatomical rat brain template.</p

Cocaine-induced brain activation: results from Bayesian fit of gamma-variate function to pharmacological MRI data.

<p>Group-wise mean ± standard deviation, <i>t</i>-value from two-sample <i>t</i>-test, and effect size (Cohen’s <i>d</i>), for two parameters calculated from Bayesian fits of a gamma-variate function to the pharmacological MRI response after intravenous cocaine injection. *<i>p</i> < 0.05, uncorrected.</p

Pharmacological magnetic resonance imaging of muscarinic acetylcholine receptor activation in rat brain

The central cholinergic system is involved in several cognitive functions such as attention, consciousness, learning and memory. Functional imaging of this neurotransmitter system may provide novel opportunities in the diagnosis and evaluation of cognitive disorders. The aim of this study was to investigate the spatial and temporal activation patterns of muscarinic acetylcholine receptor (mAChR) stimulation in rat brain with pharmacological magnetic resonance imaging (phMRI). We performed blood oxygenation level-dependent (BOLD) MRI and contrast-enhanced cerebral blood volume (CBV)-weighted MRI combined with injection of pilocarpine, a non-selective mAChR agonist. BOLD and CBV responses were assessed after pretreatment with methyl-scopolamine in order to block peripheral muscarinic effects. Region-of-interest analysis in individual animals and group-level independent component analysis failed to show significant BOLD signal changes following pilocarpine injection. However, with contrast-enhanced CBV-weighted MRI, positive CBV responses were detected in the cerebral cortex, thalamus, and hippocampus whereas a negative CBV response was observed in the striatum. Thus, pilocarpine-induced significant activation responses in brain regions that are known to have a high density of muscarinic receptors. Our study demonstrates that phMRI of mAChR stimulation in rats allows functional assessment of the cholinergic system in vivo

In Vivo Molecular MRI of ICAM-1 Expression on Endothelium and Leukocytes from Subacute to Chronic Stages After Experimental Stroke

Molecular MRI allows in vivo detection of vascular cell adhesion molecules expressed on inflamed endothelium, which enables detection of specific targets for anti-neuroinflammatory treatment. We explored to what extent MR contrast agent targeted to intercellular adhesion molecule-1 (ICAM-1) could detect endothelial- and leukocyte-associated ICAM-1 expression at different stages after experimental stroke. Furthermore, we assessed potential interfering effects of ICAM-1-targeted contrast agent on post-stroke lesion growth. Micron-sized particles of iron oxide (MPIO) functionalized with control IgG (IgG-MPIO) or anti-ICAM-1 antibody (αICAM-1-MPIO) were administrated at 1, 2, 3, 7, and 21 days after unilateral transient middle cerebral artery occlusion in mice, followed by in vivo MRI and postmortem immunohistochemistry. αICAM-1-MPIO induced significant contrast effects in the lesion core on post-stroke days 1, 2, and 3, and in the lesion borderzone and contralesional tissue on post-stroke day 2. αICAM-1-MPIO were confined to ICAM-1-positive vessels and occasionally co-localized with leukocytes. On post-stroke day 21, abundant leukocyte-associated αICAM-1-MPIO was immunohistochemically detected in the lesion core. However, MRI-based detection of αICAM-1-MPIO-labeled leukocytes was confounded by pre-contrast MRI hypointensities, presumably caused by phagocytosed blood remains. IgG-MPIO did not induce significant MRI contrast effects at 1 h after injection. Lesion development was not affected by injection of αICAM-1-MPIO or IgG-MPIO. αICAM-1-MPIO are suitable for in vivo MRI of ICAM-1 expression on vascular endothelium and leukocytes at different stages after stroke. Development of clinically applicable MPIO may offer unique opportunities for MRI-based diagnosis of neuroinflammation and identification of anti-inflammatory targets in acute stroke patients

Experimental focal neocortical epilepsy is associated with reduced white matter volume growth : results from multiparametric MRI analysis

Focal epilepsy has recently been associated with remote white matter damage, including reduced white matter volume. Longitudinal assessment of these white matter changes, in relation to functional mechanisms and consequences, may be ideally done by in vivo neuroimaging in well-controlled experimental animal models. We assessed whether advanced machine learning algorithm models could accurately detect volumetric changes in white matter from multiparametric MR images, longitudinally collected in a neocortical focal epilepsy rat model. We measured classification accuracy in two supervised segmentation models: i.e. the generalized linear model and the nonlinear random forest model-by comparing computed white matter probabilities with actual neuroanatomically identified white matter. We found excellent overall discriminatory power for both models. However, the random forest model demonstrated a superior goodness-of-fit calibration plot that was close to the ideal calibration line. Based on this model, we measured that total white matter volume increased in young adult control and epileptic rats over a period of 10 weeks, but the average white matter volume was significantly lower in the focal epilepsy group. Changes in gray matter volume were not significantly different between control and epileptic rats. Our results (1) indicate that recurrent spontaneous seizures have an adverse effect on global white matter growth and (2) show that individual whole brain white matter volume can be accurately determined using a combination of multiparametric MRI and supervised segmentation models, offering a powerful tool to assess white matter volume changes in preclinical studies of neurological disease